ARRHYTHMOGENIC RIGHT VENTRICULAR cardiomyopathy (ARVC) is a dangerous cardiac condition that can cause sudden death. Characterized by a severely thinned and dilated right ventricle, ARVC results in abnormal contractions and blood ejection, as the ventricle walls are replaced by fibro-fatty tissue. In an athlete whose ventricle reaches maximal exertion, ARVC can cause sudden death. Accurate and early diagnosis of ARVC is crucial to prevent death.
One patient's experience
Lorenzo Lopez, 39, was driving when he experienced sudden onset of chest pain, dizziness, and diaphoresis. He pulled into a medical center and collapsed in the ED. Hospital staff immediately performed CPR and defibrillation, which restored a normal sinus rhythm.
Mr. Lopez's medical history was significant only for mild hypertension, but several family members had died of sudden cardiac death. He was admitted to the hospital and underwent a series of tests, which included a right ventricular (RV) angiogram, a cardiac biopsy, magnetic resonance imaging (MRI), a signal-averaged ECG, exercise stress testing, serial daily ECGs, and an electrophysiology study.
Based on genetic testing, Mr. Lopez was diagnosed with ARVC. Before being discharged, he was given an automated implantable cardioverter defibrillator (ICD) to protect against subsequent malignant ventricular dysrhythmias associated with ARVC.
ARVC, also known as arrhythmogenic right ventricular dysplasia (ARVD), is a type of cardiomyopathy.1 Genetic testing can identify mutations responsible for these disorders. Although genetic testing and technology have yielded results in discovering aspects of ARVC, more research is required to understand this rare, yet deadly, condition.
ARVC was first described in 1977 in France. Fontaine and colleagues provided an anatomical and clinical description of several cases of ARVC that were revealed during surgical management of ventricular dysrhythmias, specifically ventricular tachycardia (VT).2 They noted patients were experiencing VT, which arose from the right ventricle with microscopic fatty and fibrous tissue within the myocardium. The condition was called ARVD because it was thought to be caused by abnormal development of the right ventricle.2
New insights into the molecular and clinical aspects of the disease have since been discovered. The condition was seen frequently on postmortem exams in young adults, specifically young athletes.2 A familial tendency was also recognized. After discovering the genetic link with ARVD, the condition was then referred to as ARVC because of the associated cardiomyopathy.1,3
Prevalence and incidence rate
One in every 5,000 people has ARVC, and the condition is responsible for about 5% of the sudden deaths of young athletes in the United States each year.3 ARVC accounts for about 17% of all sudden cardiac deaths in young adults. ARVC is one of the most common causes of sudden cardiac death in Italy, accounting for 40 of 10,000 deaths.3
ARVC is seen predominantly in men, and 30% to 50% of those with ARVC have an associated familial distribution. In the United States, the incidence rate of ARVC is about 1 in 10,000 in the general population.1,3 However, as research in this area grows, some studies suggest that ARVC may be as common as 1 in 1,000.3
Signs and symptoms of ARVC include palpitations, chest pain, presyncope, syncope, sudden cardiac death, mental confusion, anxiety, and panic attacks. Up to 80% of people with ARVC develop syncope or sudden cardiac death as an initial symptom, especially after strenuous activities. Because of the right ventricular outflow tract (RVOT) tachycardia associated with this condition, some patients may initially experience presyncope, chest pain, and palpitations. As ARVC progresses and left ventricular (LV) failure develops, the patient develops lower extremity edema, increased abdominal girth, dyspnea on exertion, and orthopnea. Although ARVC has been reported in infants, symptoms usually are first noted in adolescence.3,4
Naxos disease, an autosomal recessive variant of ARVC, occurs in more than 90% of the population on the Greek island of Naxos. The disease is described as a triad of ARVC; wooly, curly hair; and palmoplantar keratoderma. Patients with sudden cardiac death may have comparable familial genetic mutations.
Although the exact cause of ARVC is unknown, apoptosis (programmed cell death) appears to play a large role in the development of this cardiomyopathy. The disease process starts in the epicardial region and works toward the endocardial surface of the myocardium. Because the condition includes transmural involvement, many clinicians believe it could cause associated RV aneurysmal development. Aneurysmal dilation is noted in 50% of postmortem ARVC cases.1,5
This triad of dysplasia in ARVC includes the diaphragmatic, apical, and infundibular regions. As the disease progresses, LV involvement occurs and decreased LV systolic function is noted, with subsequent LV dilation as disease severity progresses. Decreased LV function usually occurs secondary to RV wall thinning; 50% to 67% of people have LV involvement. If LV involvement is noted, the patient has a poor prognosis.1,3 (See Four stages of ARVC.)
Two specific pathologic patterns are seen in ARVC. Both fatty and fibro-fatty infiltration of the RV are consistently noted. Initially, the myocardium is partially or nearly completely substituted with fatty tissue. Wall thinning doesn't seem to be associated with this process. The apical and infundibular regions of the RV seem to be most affected with the fatty infiltration.6,7 Fibro-fatty infiltration is also seen in ARVC.
Fibro-fatty tissue replaces myocytes within the RV inflow and outflow tracts, and the RV apex. Patchy myocarditis develops in 75% of cases, with inflammatory infiltrates noted on microscopic exams.6,8,9 Myocardial atrophy develops and causes thinning of the RV-free wall (less than 3 mm). The LV-free wall and ventricular septum are rarely involved. However, any anatomical area that develops the fibro-fatty infiltrates seems to be more prone to aneurysm development.6
Exercise is a contributing factor to the development of ventricular dysrhythmias associated with ARVC. Also, any condition that can cause catecholamine surges-exercise, dehydration, stress, cocaine, or electrolyte imbalances-can also be a predicating factor for malignant VT.1
ARVC is a rare disorder that needs specialized cardiology and electrophysiology consultation. Useful diagnostic tools include the ECG, including signal-averaged ECG, echocardiograph, cardiac MRI, and RV angiography.
Other diagnostic tests include an ambulatory ECG and exercise stress testing. These tests can determine conduction abnormalities and the frequency and duration of ectopic beats or ventricular dysrhythmias with day-to-day activities or exercise.
|Diagnostic criteria for ARVC|
Common diagnostic findings in ARVC include:
* ECG abnormalities. Ninety percent of patients have some abnormality, typically T-wave inversions in leads V1 to V3. Right bundle-branch block also may occur, and some patients may have an epsilon wave secondary to slowing of intraventricular conduction. This wave is seen as a terminal notch in the QRS complex, and most often is seen on a signal-averaged ECG.
* Echocardiographic abnormalities. RV dilation, hypokinesis, and a paper-thin RV-free wall are typical. Tricuspid regurgitation may occur secondary to dilation of the RV annulus.
* RV-free wall changes on cardiac MRI. Fatty infiltration, thinning, and akinesis of the RV-free wall are typical.
* Abnormalities on RV angiography. Akinetic or dyskinetic bulging may be localized in the triad of dysplasia areas (infundibular, apical, and subtricuspid). This test is observer-dependent, but has 90% specificity.
For a clinician to arrive at a definitive diagnosis of ARVC, two major criteria or one major and two minor criteria must be present, or four minor criteria from different groups. (See Diagnostic criteria for ARVC.)
Medical management of ARVC is complex. Medications to control heart rate and VTs, such as beta-adrenergic blockers (for example, sotalol) or amiodarone, may be prescribed. The patient should be hospitalized at the start of treatment with sotalol for cardiac dysrhythmia monitoring and evaluation of renal function. Obtain a baseline QT interval and calculation of creatinine clearance before administering medications. Patients receiving amiodarone need to be monitored closely for adverse reactions (including corneal microdeposits, optic neuropathy, thyroid dysfunction, and photosensitivity) and pulmonary and hepatic toxicity. If the patient has concomitant RV dyskinesis, warfarin may also be used to prevent embolic development secondary to high residual blood volume in the right ventricle.9
ICD placement is commonly performed in patients with ARVC, but extreme caution must be used because wall thinning puts patients at high risk for RV perforation. Ablation of the reentry tracts associated within the RV outflow tract is often performed as well.9
ARVC is primarily an autosomal dominant genetic disorder, which means there is a 50% chance offspring will develop ARVC or its symptoms. However, autosomal recessive cases of ARVC have also been noted, with Naxos disease being one example.
As with other genetic dominant disorders, ARVC has a wide variability of expression in families. This means that not all families have the same presentation of the disorder, even though the genetic mutation is similar in all cases.5,8
In Mr. Lopez's case, his genetic profile showed two genetic mutations, specifically plakoglobin and plakophilin.6 His case was autosomal recessive, so his children would have a 50% chance of developing ARVC.1,7,9
Wertz and colleagues, writing in the early 1990s, discouraged testing children for adult-onset genetic conditions, suggesting that children might be labeled or treated differently depending on test results, or suffer psychologic harm.10 As a result, for many years practitioners didn't feel comfortable encouraging genetic testing in children for conditions that may only manifest in adulthood, and many possibilities for treatment and management modalities were missed. Healthcare providers should talk candidly with parents about genetic testing and weigh both sides of the argument for genetic testing before engaging in therapies and treating patients who may have genetic abnormalities.11
To address patients' fears that insurers and employers would use genetic information against patients, the federal Genetic Information Non-Discrimination Act became law in May 2008. The law prohibits using genetic information in the process of obtaining employment or health insurance.12
Risk versus benefit should be explored with patients and parents, including risk of labeling as well as consequences of not receiving testing. Testing exclusively for documentation purposes is controversial, especially related to genetics. Before counseling and genetic testing, practitioners must decide how the information will be beneficial to treatment. Practitioners must be patient and allow time for questions when approaching parents regarding possible genetic testing. Practitioners should have a well-designed rationale for suggesting genetic testing.
Financial constraints may also play a role among parents who choose not to have genetic testing. Practitioners should conduct precounseling research to determine possible funding for genetic testing if the patient's family can't afford it. The National Institutes of Health and other agencies sometimes provide free testing. Practitioners can also contact national organizations that specialize in the genetic disorder to determine possible funding sources for testing.
Perform thorough physical assessments, family histories, and genetic pedigrees in young adults undergoing physicals for competitive and contact sports. Although rare, ARVC has a high mortality, so investigate the possibility of familial tendencies in young adults.
During the exam, elicit information from the patient about a family history of palpitations, lightheadedness, or blackouts during young adulthood. This information is consistent with ARVC and further investigation is necessary. Conduct a thorough review of systems and ask the patient about a personal history of palpitations, lightheadedness, unexplained fatigue, and diaphoretic episodes not associated with sports and chest pain.
Review genetic testing and associated ethical considerations with the patient and family. Because of the higher incidence of ARVC in Italians and those with Naxos disease characteristics, patients of Mediterranean heritage should be urged to get genetic testing. Family history should focus on age of onset of cardiac disease and length of symptoms, if any, before a cardiac event. Age and cause of death should always be clarified.5
Ask about the patient's environmental exposures and medications, to help distinguish among congenital, genetic, and acquired forms of heart disease. Record dates and results of cardiovascular tests, procedures, surgeries (ICD, transplantation), as well as genetic testing in the family history.
Proper construction of a family pedigree is essential to diagnosis and counseling. Pedigrees should include at least three generations, including maternal and paternal sides of the family, and the patient's siblings, mother, father, aunts, uncles, grandparents, and children. Note any episode of sudden death, sudden cardiac death (including sudden myocardial infarction before age 50), syncope, presyncope, palpitations, and dysrhythmias.
After positive diagnosis of ARVC, patients should avoid strenuous activity and refrain from participating in competitive or contact sports. Although limited data are available about ARVC-associated symptoms in pregnancy, no contraindication from becoming pregnant has been noted. However, patients should be encouraged to have genetic testing performed before conceiving.1
Remember to address the psychologic ramifications of ARVC-anxiety, panic attacks, and depression are common. Counseling, medication, and other interventions should be individualized for each patient. Because of the high genetic penetrance associated with ARVC, patients should receive individual counseling regarding genetic testing for other family members. Early identification of genetic mutations can dramatically decrease the risk of sudden cardiac death and the consequences associated with RV functional deterioration.
Any patient suspected of having ARVC or symptoms that suggest this condition should be referred to a center that specializes in electrophysiologic abnormalities. Specialized resources and diagnostic tools are necessary to properly diagnose and manage this disorder. These patients will likely need long-term, specialized follow-up, so early access to these resources is helpful.4
Because ARVC was only identified some 30 years ago, little is known about the disease process. Continued research and interdisciplinary approaches to patients and families when attempting to diagnose this disorder are paramount. Meticulous clinical evaluation and family history, genetic testing and counseling, and risk stratification should be performed on young adults who want to participate in contact sports and also have a personal or family history of syncope or sudden cardiac death.
By understanding ARVC and its genetic underpinnings, you can help your patient get appropriate care and counseling.
Four stages of ARVC
Subtle structural changes in the RV. Patient usually asymptomatic, although may have minor VT. High risk of sudden death.
Noticeable structural or functional changes in the RV. Symptoms include ventricular dysrhythmias, presyncope, syncope, and palpitations.
Weakening of the RV
RV dilates and weakens. Symptoms of RV failure include edema of the legs or ankles, abdominal distension, dyspepsia, and anorexia.
Weakening of the LV
LV dilates and weakens. Symptoms of heart failure include dyspnea on exertion, orthopnea, and breathlessness.
Source: Cardiomyopathy Association. http://www.cardiomyopathy.org.